1. Field of the Invention
The present invention relates to a transnasal anticonvulsive pharmaceutical composition comprising a poorly soluble anticonvulsant, and more particularly, to a transnasal anticonvulsive pharmaceutical composition having enhanced bioavailability to be effectively delivered at a therapeutic dose, and improved viscosity and/or enhanced solubility to show desirable properties such as spray angle and spraying shape.
2. Description of the Prior Art
Status epilepticus is a neurologically emergent condition, leading to 3-35% mortality. The chief target for treatment of status epilepticus is to swiftly manage pathological attacks. However, when the symptoms of status epilepticus last for a long time without swift management, it is difficult to control the status epilepticus, and the risk of permanent brain damage increases. Therefore, it is very important to swiftly treat patients by administering an adequate dose of a pharmaceutical composition having an adequate pharmaceutical formulation containing an effective drug.
Recently, it has been known that a variety of pharmacotherapies are used to treat status epilepticus. Diazepam and lorazepam are benzodiazepine drugs that have been most widely used for this purpose. Also, the intravenous administration of an anticonvulsant is the swiftest way to suppress epileptic convulsions. However, when the intravenous administration is not easy, for example, when the intravenous administration is delayed due to technical difficulties, such as the lack of a sterilizer and a skilled practitioner, and when there is phlebitis to possibly develop, it may be more desirable to administer an anticonvulsant via other routes. Also, intravenous drugs are often associated with hypotension, cardiac dysrhythmia or central nervous system degeneracy. In this regard, Moolenar, et al. made an attempt to administer diazepam to human beings via various routes such as intramuscular injection, oral tablet and rectal solution (Int. J. Pharm., 5: 127-137 (1986)), but they found that the rectal administration of the diazepam provides its highly swift absorption. Therefore, it may be considered that rectal administration be used as an alternative to an intravenous injection. Kenneth L., et al. has developed the rectal formulation (U.S. Pat. No. 5,462,740) as a useful method. This rectal route of administration is a very uncomfortable route used for the emergency treatment and the drug administration to patients with age over the adolescent period.
Nasal mucosae provide a virtual route for therapeutic effects of many medicinal substances. Nasal administration has an advantage in that drugs may be easily and simply administered to achieve systemic or topical effects, when necessary. In particular, zolmitriptan (U.S. Pat. No. 5,466,699), which had been developed as one of drugs for the central nervous system to treat migraine, was developed and commercially available as a nasal spray formulation (U.S. Pat. No. 6,750,237), and sumatriptan (U.S. Pat. No. 5,037,845) was also developed and commercially available as a nasal spray. However, unlike thse two water-soluble drugs, most drugs hardly have solubility corresponding to a desired therapeutic dose, and one leading problem associated with the nasal administration of drugs may not be solved by the simple transnasal administration means since most of the drug molecules are not easily or are slowly spread through the nasal mucosae. An additional restriction on the nasal administration of drugs is that the drugs are restrictedly administered in a small dose. In general, it is impossible to administer drugs in a dose of approximately 150 ul or more per nostril, and an amount of a mixture exceeding the dose range of the drugs are extruded into the pharynx, and swallowed.
Also, the drugs such as diazepam and lorazepam are difficult to be developed into a formulation suitable for nasal spray administration since they have low solubility in water that is widely used to dissolve drugs. Therefore, the development of solvents for nasal spray administration, which dissolve a desired drug, for example, diazepam and lorazepam, in a high concentration and give no stimulus to the nasal mucosae, is highly required.
The nasal absorption of drugs may be augmented by administering the drugs and a chemical aid or a penetration enhancer at the same time. For example, Lau and Slattery [Lau, et al., Int. J. Pharm., 54: 171-174 (1989)] made an attempt to dissolve a benzodiazepine (i.e. diazepam) in various solvents (for example, triacetin, dimethyl sulfoxide, PEG 400, Cremophor EL, Lipal-9-LA, diisopropyl adipate and azone) and administer the dissolved drug.
However, the diazepam was dissolved in most of the solvents within a desired concentration, but the desired concentration of the solvents is too pungent to be used for transnasal administration. Cremophor EL has been known to have the lowest stimulus to the nasal mucosal tissue, but its nasal absorption is rather slow (Tmax: 1.4 hours) in humans in use of these vehicles, and the peak concentration is lower than that observed after the intravenous administration. Recently, Li, et al. (International Journal of Pharmaceutics Vol. 237, pp 77-85, 2002) proposed a microemulsion for rapid-onset transnasal delivery of diazepam.
Also, U.S. Pat. No. 6,627,211 B1 (KR 2002-0059583) discloses transnasal anticonvulsive compositions comprising diazepam. Here, the diazepam is dissolved in a soluble formulation such as aliphatic alcohol, a polar solvent (i.e. glycol), water, etc. Also, published US patent application No. 2005-0002987 A1 (KR 2006-0012030) discloses microemulsions containing diazepam used for transnasal administration. Here, the diazepam is dissolved in a vehicle comprising equivalent amounts of fatty acid ester and water and the balance of hydrophilic surfactant, polar solvent (i.e. glycol), etc.
When drugs are nasally administered to patients, their fine and uniform dispersion is important. A spraying shape test used to evaluate the efficiency of a nasal spraying agent has been widely used to evaluate a nasal administration formulation in vitro. This spraying shape test is important since the in vivo delivery of a drug is possible when the drug uniformly distributed following its nasal spraying. For example, USA test standards on the spraying shape test has been set, and must be reproducible and be suitable for these test standards in order to deliver a suitable drug to treat its corresponding disease (U.S. Food and Drug Administration's (FDA) Draft Guidance for Industry: Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Spray for Local Action (June 1999).
According to the report by Yang, et al. (Pharmaceutical Research Vol 22, No. 11, pp. 1871-1878, 2005), a formulation having a small droplet size and low viscosity is delivered to central and inner regions of the nasal cavities, which indicates that the formulation is more desirably distributed nasally than formations having a big droplet size and high viscosity. Therefore, it is important that the nasal formulation has a viscosity and droplet size suitable for the purpose of drug delivery. There is a significant need for a pharmaceutical composition having physical properties suitable for transnasal administration, such as enhanced bioavailability of a poorly soluble anticonvulsant, viscosity and/or solubility, etc.
Such compositions are provided in accordance with the present invention. Further, the present invention provides a method for treating convulsions including: administering to patients suffering from the convulsions a sufficient amount of a pharmaceutical composition to treat the convulsions.